Annals of the New York Academy of Sciences, vol. 1085, 2006
The Annals of the New York Academy of Sciences based on the papers presented at the
International Symposium on AAA Pathobiology in April 2006 has gone to press. Hard copy
will hopefully be available before the end of this year (2006). There are 50 chapters in the book. The book was edited by Dr. Tilson, with
Drs. G.R.Upchurch, Jr, and H.Kuivaniemi as diligent and expert Co-Editors.
I contributed one platform paper as first author and two extended poster abstracts. I
also contributed some welcoming remarks, and the Keynote Address was given by M. Wassef
of the NIH/NHLBI.
Tilson MD, Ro C: The Candidate Gene Approach to
Susceptibility for Abdominal Aortic Aneurysm (AAA): TIMP1, HLA-DR-15, Ferritin Light Chain (FTL), and Collagen XI-Alpha-1 (COL11A1.
Tilson MD: Features and Genomic Origins of Matrix Cell Adhesion Molecules 1 and 2 (Mat-CAM-1 and Mat-CAM-2)
Expressed by Fibroblasts of Human Aortic Adventitial Origin.
Tilson MD, Withers L.: Arterial Aneurysms in HIV Patients.
Molecular Mimicry Versus Direct Infection?
Revisions to three GenBank Flatfiles, December 2006
The first two revisions are simple, and the flatfiles of the reported nucleotide sequences are
unchanged. The revisions update our recent interpretations of the biological significance of
Cytochrome b mutation.
A mutation in a mitochondrial DNA may explain maternal transmission of
AAA susceptibility. In 2001 we reported a sequence for cytochrome b, from a cDNA library derived from
aortic fibroblasts of a patient with AAA. Ever since 1984,
when I wrote a paper (with Margreta Seashore of Yale Univ) on patterns of clustering of affected AAA patients
in families, I have been perplexed by a phenomenon which we described at the time as "X-linked Dominant Inheritance"
(for lack of a more definitive term). We know now that cytochrome b is a mitochondrial DNA sequence,
so that it would be inherited by all children of a mother with AAA. In the context of increasing
interest in oxidative injury as a component of AAA pathobiology, and of new
knowledge about the role of the mitochondrion in inducing pathways to apoptosis, the observation of a mutation in
cytochrome b takes on novel potential interest. If a dud cytochrome b interferes with electron transfer by
Complex III, the mitochondrion might be showering the cytoplasm of the aortic adventitial fibroblast with
free radicals. A title under consideration for a manuscript in preparation is: "Black Widow Syndrome - The Aneurysm
Susceptibility 'gene may be rampant in those families where a woman is the index case' - BLAT Build Mar 2006 chrM
#15520 T>C => codon change Leu(19)Pro in Cytochrome b"
Matrix Cell Adhesion Molecule-1 (MatCAM-1)
This revision is to the title of a manuscript in preparation (tagged "unpublished"). based
on the sequence of Matrix Cell Adhesion Molecule-1 (MatCAM-1). We now understand that the N-terminal domains
of some Ig-like repeats in members of the cadherin family of cell-cell
adhesion molecules feature reactive tryptophan residues in the loops exposed at the turns of the anti-
parallel folds of the Ig-sheets. These residues are involved in domain switching across cells to
establish adhesion in contiguities like desmosomes. We now observe that there is a "W" in a loop near the N-terminus of
Mat-CAM-1. We also have immunohistochemical evidence that the C-terminal domain is anchored in the
matrix of the adventitial collagen/elastin associated microfibrils of the aortic adventitia. Thus, the "W" in
the Mat-CAM-1 may enable a switch-domain to bind to a cellular cadherin, providing a biochemical
basis for matrix <-> cell adhesion. A title under consideration for a manuscript in preparation is "Trp (16)
in Precursor mRNA sequence for Matrix Cell Adhesion Molecule-1 (Mat-CAM-1) May Provide An Additional Basis for
Adhesion to Cell-Surface Cadherins".
Mutations of Collagen XI-alpha-1 These revisions involve several sequences with possible mutations in the aorta-specific, alternatively-
spliced, Exon 6A of Collagen XI-alpha. From the initial sequencing data on the genomic DNA from specimens with
AAA, the computer analytical program read several heterozygous polymorphisms, which we confirmed by
visual inspection of the chromatographic runs. This work was repeated by my Post-Doctoral Student Charles Ro
(2004-2005), who used primers that were more widely spaced to include the flanking introns of Exon 6A. The sequence data
were of much higher quality and led to the conclusion that we had misinterpreted the initial apparent heterozygosities
in Exon 6A. However, on those runs, there was an unambiguous substitution -70bp upstream in the intron preceding
6A in 14 consecutively sequenced AAA patients. This polymorphism may be in a promotor region. We are presently updating the
previously reported Exon 6A sequences; and in addition, we are reporting sequences from new specimen acquisitions
that exhibit the same heterozygosity.